Isomigrastatin analogs in the treatment of cancer
View Patent ↗The present invention provides compounds having formula (I): (I) wherein n, R 1 -R 5 , R a -R b , Q, Y 1 and Y 2 are as defined herein; and additionally provides methods for the synthesis thereof, compositions thereof, and methods for the use thereof in the treatment of various disorders including cancer, metastasis and disorders involving increased angiogenesis.
1. An isolated compound having the structure:
or pharmaceutically acceptable salt, amide, or ester thereof;
wherein n is an integer from 1 to 4;
R 1 and R 2 are each independently hydrogen, an aliphatic moiety, or an aromatic moiety;
R 3 is hydrogen, halogen, aliphatic, heteroaliphatic, alicyclic, heterocyclic, aryl or heteroaryl moiety, or —WR 3A ; wherein W is independently —O—, —S—, —NR 3B — or —C(═O)—, wherein R 3A is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heterocyclic, aryl or heteroaryl moiety; —C(═O)R 3C , —Si(R 3C ) 3 , —C(═S)R 3C , —C(═NR 3C )R 3C , —SO 2 R 3C , or —ZR 3C , wherein Z is —O—, —S—, —NR 3D , wherein each occurrence of R 3B , R 3C and R 3D is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heterocyclic, aryl or heteroaryl moiety;
R 4 is halogen, —OR 4A , —OC(═O)R 4A or —NR 4A R 4B ; wherein R 4A and R 4B are independently hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; a nitrogen protecting group or an oxygen protecting group; or R 4A and R 4B , taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or R 4 , taken together with the carbon atom to which it is attached forms a moiety having the structure:
R 5 is hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R a is independently hydrogen, —CN, —S(O) 1-2 R a1 , —NO 2 , —COR a1 , —CO 2 R a1 , —NR a1 C(═O)R a2 , NR a1 C(═O)OR a2 , —CONR a1 R a2 , or an aliphatic moiety, wherein each occurrence of R a1 and R a2 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety;
R b is independently hydrogen, an aliphatic moiety, or an aromatic moiety;
X 1 is O, or S;
Q is hydrogen, halogen, —CN, C 1-6 aliphatic optionally substituted with halogen, C 1-6 heteroaliphatic, or —WR Q1 ; wherein W is independently —O—, —S— or —NR Q3 —, wherein each occurrence of R Q1 and R Q3 is independently hydrogen or C 1-6 alkyl;
Y 1 and Y 2 are independently hydrogen, an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; or —WR Y1 , wherein W is independently —O—, —S— or —NR Y2 —, and each occurrence of R Y1 and R Y2 is independently hydrogen, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure:
2. The compound of claim 1 , wherein:
R 1 and R 2 are each independently hydrogen or substituted or unsubstituted lower alkyl;
R 3 is hydrogen, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety, or —WR 3A ; wherein W is independently —O—, —S—, —NR 3B — or —C(═O)—, wherein R 3A is hydrogen, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety; —C(═O)R 3C , —Si(R 3C ) 3 , —C(═S)R 3C , —C(═NR 3C )R 3C , —SO 2 R 3C , or —ZR 3C , wherein Z is —O—, —S—, —NR 3D , wherein each occurrence of R 3B , R 3C and R 3D is independently hydrogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
R 4 is halogen, —OR 4A , —OC(═O)R 4A or —NR 4A R 4B ; wherein R 4A and R 4B are independently hydrogen, or substituted or unsubstituted lower alkyl; a nitrogen protecting group or an oxygen protecting group; or R 4A and R 4B B, taken together with the nitrogen atom to which they are attached, form a heterocyclic or heteroaryl moiety; or R 4 , taken together with the carbon atom to which it is attached forms a moiety having the structure:
R 5 is hydrogen or substituted or unsubstituted lower alkyl;
R a is independently a hydrogen or an alkyl moiety;
R b is independently hydrogen, alkyl, an aryl moiety or a heteroaryl moiety;
X 1 is O, or S;
Y 1 and Y 2 are independently hydrogen, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety; or —WR Y1 , wherein W is independently —O—, —S— or —NR Y2 —, and each occurrence of R Y1 and R Y2 is independently hydrogen, or an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety; or Y 1 and Y 2 together with the carbon atom to which they are attached form a moiety having the structure:
3. The compound of claim 2 , wherein the compound has one of the following structures:
wherein W is O or NH; and R Y1 is independently an aryl or heteroaryl moiety.
4. The compound of claim 3 , wherein Q is hydrogen.
5. The compound of claim 2 , wherein R a and R b are each hydrogen, Q is hydrogen and the compound has the following structure:
6. The compound of claim 2 , wherein Y 1 , Y 2 , R a and R b are each hydrogen, Q is hydrogen, and the compound has the following structure:
7. The compound of claim 2 , having the following structure:
wherein R 3A is hydrogen, lower alkyl or lower acyl.
8. The compound of claim 2 , having the following structure:
9. The compound of claim 2 , having the structure:
wherein Y 1 and Y 2 are independently hydrogen or alkyl.
10. The compound of claim 2 , having the structure:
wherein R 4A is hydrogen or lower alkyl.
11. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.
12. The compound of claim 1 , wherein R 5 is methyl.
13. The compound of claim 1 , wherein R 3 is lower alkoxy.
14. The compound of claim 13 , wherein R 3 is methoxy.
15. The compound of claim 1 , wherein R 4 is OH, OAc, NH 2 or halogen, or R 4 taken together with the carbon atom to which it is attached forms a moiety having the structure:
16. The compound of claim 1 , wherein the stereocenter
has the following stereochemistry
17. The compound of any one of claim 1 , wherein the stereocenter
has the following stereochemistry
18. The compound of claim 1 having the structure:
19. The compound of claim 1 having the structure:
20. A pharmaceutical composition comprising:
a pharmaceutically acceptable carrier, adjuvant or vehicle; and
a compound of claim 1 .
21. The pharmaceutical composition of claim 20 wherein the compound is present in an amount effective to inhibit the metastasis of tumor cells.
22. The pharmaceutical composition of claim 20 wherein the compound is present in an amount effective to inhibit angiogenesis.
23. The composition of claim 20 , further comprising a cytotoxic agent.
24. The composition of claim 23 , wherein the cytotoxic agent is an anticancer agent.
25. The composition of claim 24 , wherein the anticancer agent is 12,13-desoxyepothilone B, (E)-9,10-dehydro-12,13-desoxyEpoB, 26-CF3-(E)-9,10-dehydro-12,13-desoxyEpoB, taxol, radicicol or TMC-95A/B.
26. The composition of claim 20 , further comprising a palliative agent.
27. A method for treating or lessening the severity of metastasis of tumor cells in a subject comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a composition according to claim 20 ;
wherein the compound of claim 1 or composition of claim 20 inhibits metastasis of ovarian or colon tumor cells; and
wherein said method optionally further comprises a cytotoxic agent.
28. The method of claim 27 , wherein the cancer is a solid tumor.
29. The method of claim 27 , wherein the cytotoxic agent is an anticancer agent.
30. The method of claim 29 , wherein the anticancer agent is 12,13-desoxyepothilone B, (E)-9,10-dehydro-12,13-desoxyEpoB, 26-CF3-(E)-9,10-dehydro-12,13-desoxyEpoB, taxol, radicicol or TMC-95A/B.
31. The method of claim 27 , further comprising administering a palliative agent.
32. A method for treating or lessening the severity of cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 or a composition according to claim 20
wherein the cancer is ovarian or colon.
33. The method of claim 32 , wherein the dosage is between about 0.1 mg/kg to about 50 mg/kg of body weight.
34. The method of claim 32 , wherein the dosage is between about 0.1 mg/kg to about 40 mg/kg of body weight.
35. The method of claim 32 , wherein the dosage is between about 0.1 mg/kg to about 30 mg/kg of body weight.
36. The method of claim 32 , wherein the dosage is between about 0.1 mg/kg to about 20 mg/kg of body weight.
37. The method of claim 32 , wherein the dosage is between about 1 mg/kg to about 50 mg/kg of body weight.
38. The method of claim 32 , wherein the dosage is between about 1 mg/kg to about 40 mg/kg of body weight.
39. The method of claim 32 , wherein the dosage is between about 1 mg/kg to about 30 mg/kg of body weight.
40. The method of claim 32 , wherein the dosage is between about 1 mg/kg to about 20 mg/kg of body weight.
41. The method of claim 32 , wherein the dosage is between about 5 mg/kg to about 50 mg/kg of body weight.
42. The method of claim 32 , wherein the dosage is between about 5 mg/kg to about 40 mg/kg of body weight.
43. The method of claim 32 , wherein the dosage is between about 5 mg/kg to about 30 mg/kg of body weight.
44. The method of claim 32 , wherein the dosage is between about 5 mg/kg to about 25 mg/kg of body weight.
45. The method of claim 32 , wherein the dosage is between about 10 mg/kg to about 50 mg/kg of body weight.
46. The method of claim 32 , wherein the dosage is between about 10 mg/kg to about 40 mg/kg of body weight.
47. The method of claim 32 , wherein the dosage is between about 10 mg/kg to about 30 mg/kg of body weight.
48. The method of claim 32 , wherein the dosage is between about 10 mg/kg to about 20 mg/kg of body weight.
49. The method of claim 32 , wherein the dosage is 10 mg/kg or greater of body weight.
50. The method of claim 32 , wherein the cancer is ovarian cancer.
51. The method of claim 50 , wherein the compound is present in an amount effective to inhibit metastasis of ovarian tumor cells.
52. The method of claim 32 , further comprising a cytotoxic agent.
53. The method of claim 52 , wherein the cytotoxic agent is an anticancer agent.
54. The method of claim 32 , further comprising a palliative agent.
55. The method of claim 32 , wherein the composition is administered at a dosage between about 10 mg/kg to about 20 mg/kg of body weight.
56. The method of claim 51 , further comprising administering a cytotoxic agent.
57. The method of claim 56 , wherein the cytotoxic agent is an anticancer agent.
58. The method of claim 51 , further comprising administering a palliative agent.
59. A compound having the structure: